Dissecting the association of autophagy-related genes with cardiovascular diseases and intermediate vascular traits: A population-based approach.

Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.